Subcutaneous implant

ABSTRACT

A non-abusable, non-inflammatory, biocompatible, non-biodegradable, subcutaneous, polymeric implant for the prolonged, controlled release of hydromorphone with near zero-order kinetics is described. Methods of alleviating cancer pain and treating opioid drug addiction with the implant are also described.

This application is a divisional of Ser. No. 08/791,404 filed Jan. 30,1997, now U.S. Pat. No. 5,858,388 which is a divisional of Ser. No.08/264,689 filed Jun. 23, 1994, now U.S. Pat. No. 5,633,000.

FILED OF THE INVENTION

This invention relates to a unique device for the chronic subcutaneousadministration of a potent opioid in a form that renders it difficult todivert for illicit use and ensures prolonged steady release of thisagent, thereby providing long term pain relief or treatment of opioiddrug addiction, and preventing the potentially lethal consequences of anuneven release of drug from the device.

BACKGROUND OF THE INVENTION

Approximately 70% of patients with cancer experience pain attributableto their neoplasm or its therapy. As life expectancy has increased indeveloped and developing countries, cancer and cancer-related pain havebecome major social and medical concerns. The worldwide availability ofopioid analgesics, the primary therapy for most cancer-related pain,varies greatly. In 1991, 20 developed countries accounted for 86% of themorphine consumed in the world while the remaining 14% of morphine wasconsumed in the remaining countries having the majority of the world'spopulation. (Joranson, D. E., Journal of Pain and Symptom Management,8(6):353-360, 1993).

The scant use of opiates for the relief of cancer pain for the majorityof the world's population is a result of many factors including concernsover drug diversion for illicit use and addiction. Further, manypatients with cancer-related pain require long-term continuous dosing ofopioid analgesics which often necessitates the ingestion of multiplepills or tablets many times a day. Compliance with this dosing scheme isoften poor. Further, enteral drug delivery is poorly tolerated orprohibited in many patients with cancer-related pain in whom continuousdrug delivery is a necessity. However, continuous parenteral delivery ofopioid analgesics is expensive, cumbersome, and dependent upon theavailability of refrigeration, catheters, pumps and trained personnel.

Drug addiction is a major societal problem throughout the world. In theUnited States alone, on any given day, there are several hundredthousand addicts who are enrolled in treatment clinics. Most of them areplaced on "methadone maintenance" as a basic part of their therapy.Major behavioral and compliance problems commonly complicate treatment.

The cost of "methadone maintenance" therapy is several hundred dollarsper month per patient. A significant portion of this cost relates to thefrequent clinic visits and the monitoring of urine tests that are run toassure proper compliance with drug dosing, as well as the pharmacycharges relating to methadone dispensing.

Delivery systems and devices for controlled release of drugs; i.e.,controlled release and sustained or prolonged release, are well known inthe art. A variety of methods have been described in the literature,including the physiological modification of absorption or excretion,modification of the solvent, chemical modification of the drug,absorption of drug on an insoluble carrier, use of suspensions andimplantation pellets. Other methods include mixing the drug with acarrier such as waxes, oils, fats, and soluble polymers which aregradually disintegrated by the environment resulting in release of thedrug. Much attention has been directed to the reservoir type of device,i.e., a device in which a drug is encased within a polymeric container,with or without a solvent or carrier, which allows passage of drug fromthe reservoir.

Another type of drug delivery device is the monolithic type in which adrug is dispersed in a polymer and from which the drug is released bydegradation of the polymer and/or by passage of the drug through thepolymer. Ethylene-vinyl acetate (EVA) copolymer is a well knownrepresentative of an imperforate polymer (Rhine, W D, et al, Journal ofPharmaceutical Sciences 69:265-270, 1980; Sefton, M. V., et al, Journalof Pharmaceutical Sciences, 73:1859-1861, 1984; Cohen, J., et al, J.Pharm. Sci., 73:1034-7, 1973). The release kinetics of a drug from apolymeric delivery system are a function of the agent's molecularweight, lipid solubility, and charge as well as the characteristics ofthe polymer, the percent drug loading, and the characteristics of anymatrix coating. The importance of these factors coupled with thespecific pharmacology, toxicology, and therapeutic goals necessitatethat the design of a polymeric implant for a specific agent must becarefully constructed.

Ku et al, J. Pharm. Sci., 74, p. 926 (1985) describe a multiple-holeapproach to obtain zero order release.

The sustained parenteral delivery of opioid antagonists and agonists hasbeen an area of considerable interest because first, it may afford a newapproach to the treatment of opioid drug abuse and second, theundertreatment of pain is widely recognized throughout the world.

A. Narcotic Antagonist: Naltrexone

Over the past two decades, a variety of approaches have been attemptedusing polymers containing narcotic antagonists in an effort to preventdrug abuse. The release characteristics of these antagonists are lesscritical than those of the pure agonists as evidenced by the first-orderkinetics noted in the literature.

1. Glycerine implants

2. Cholesterol-glyceryltriesterate demonstrated first order kinetics inrats

3. Glutamic acid and leucine--biodegradable

4. Polylacticlglycolic acid (PLGA) beads

B. Narcotic Mixed Agonist/Antagonist: Buprenorphine

First order kinetic release using an agent which is not preferred forthe treatment of chronic pain.

1. Cholesterol-glyceryltriesterate demonstrated first order kinetics inrats.

C. Narcotic Agonist: Morphine

Morphine is an excellent agent for the treatment of pain but is seventimes less potent than hydromorphone and thus, is much less suitable forlong-term subcutaneous implant. Many of these implants have demonstratedfirst-order kinetic release which would threaten the lives of patientsreceiving implants containing lethal amounts of opioids.

1. Polymeric silicone elastomer

2. Silicone with sodium alginate (swells on contact with water torelease drug)

3. Pellets

4. Polyanhydride formulation

D. EVA Implants

EVA (ethylene vinyl acetate) polymers have been used to deliver manyclasses of drugs: Hormones (i.e., prednisolone, insulin), antineoplasticagents (i.e., 5FU, adriamycin), proteins (i.e., albumin,immunogloblins), neurotransmitters (i.e., dopamine), and antibiotics. Aburst of these agents is inconsequential compared to a burst of potentopioids.

1. Prednisolone (Miyazaki, S., et al, Chem. Pharm. Bull (Tokyo),29:2714-7, 1981

2. 5FU (Wyszynski, R. E., et al, J. Ocul. Pharmacol., 5:141-6, 1989)

3. Adriamycin (Lin, S. Y., et al, Biomat Art Cells Art Org., 17:189-203,1989.

4. Insulin (Brown, L., et al, Diabetes, 35:692-7, 1986; Brown, L., etal, Diabetes, 35:684-91, 1986)--EVA coated and with hole in one face ofthe polymer giving near constant release rates.

5. Nerve Growth Factor (Hofman, D., et al, Bxp Neurol, 110:39-44, 1990)

6. Immunoglobulin (Radomsky, M. L., et al, Biomaterials, 11:619-24,1990)

7. Albumin (Niemi, S. M., et al, Lab Anim. Sci., 35:609-12, 1985)

8. Dopamine/Levodopa (During, M. J., et al, Ann. Neurol., 25:351-356,1989; Sabel, B. A., et al, Ann. Neurol., 28:714-717, 1990)

Mechanisms for making EVA polymers and tests of their biocompatibilityand non-inflammatory nature have been described in the literature.Brown, L. R., et al, J. Pharm. Sci., 72:1181-5, 1983; Langer, R., et al,J. Biomed. Mater. Res., 15:267-77, 1981; and Niemi, S. M., et al, Lab.Anim. Sci., 35:609-12, 1985, all describe the non-inflammatory nature ofthe polymer and techniques for polymer manufacture.

Critical factors involved in changing the release characteristics ofdrugs from EVA polymer have been described (Brook, I. M., et al, Br.Den. J., 157:11-15, 1984).

U.S. Pat. No. 5,153,002, hereby incorporated by reference, describes acube with 5 sides coated with impermeable layer and a cylinder with allbut one flat side coated. A hemisphere with impermeable coating(paraffin) except for exposed cavity in the center face provides zeroorder kinetics for albumin release (Hsieh,. D. S., et al, J. Pharm.Sci., 72:17-22, 1982). EVA with impermeable coating of polymer with holein the center of one face provides zero order kinetics for insulinrelease. Drug particle size, drug loading, and matrix coating allsignificantly affect release kinetics (Rhine, W. D., et al, J. Pharm.Sci., 69:265-70, 1980).

Grossman et al (Proceedings ASCO, Vol. 19, p337 (1991)) describe adelivery system where hydromorphone was embedded into a controlledrelease matrix made of poly-[ethylene-vinyl acetate].

OBJECTS OF THE INVENTION

It is an object of the invention to provide an implantable,biocompatible polymer that continuously delivers a stable concentrationof an opioid analgesic subcutaneously for periods ranging from two weeksto in excess of six months.

It is a further object of the invention to provide a means to administerthe pain reliever hydromorphone in a form which makes it difficult todivert for illicit use.

SUMMARY OF THE INVENTION

The subject invention relates to a subcutaneous delivery systemcomprising: i) a polymeric matrix material, ii) a therapeutic agentembedded in said matrix, and, iii) a coating surrounding said matrix,wherein said delivery system is adapted to provide near constantdelivery of hydromorphone.

The invention also includes a method of providing a delivery systemcomprising i) implanting a therapeutic agent in a polyethylene vinylacetate matrix, ii) forming said matrix into a cylinder, iii) coatingsaid matrix with poly(methyl methacrylate), and iv) creating acylindrical opening along the axis of the cylindrical matrix creating aninternal wall in said matrix, wherein said internal wall of said matrixhas no coating.

The invention also involves a method of providing prolonged relief ofpain in a mammal suffering from pain comprising subcutaneouslyadministering at least one device (where two or more are administered,they are joined together or separate) to said mammal, and furtherinvolves a method of treating opioid drug addiction in a mammal havingsuch an addiction comprising subcutaneously administering at least onedevice to said mammal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a delivery device according to theinvention.

FIG. 2 is a cross-sectional view of a delivery device taken along line2--2 of FIG. 1. The thickness of the coating has been exaggerated forillustrative purposes.

FIG. 3 is a perspective view of the hemisphere embodiment of theinvention.

FIG. 4 is a perspective view of the cube embodiment of the invention.

FIG. 5 is a perspective view of the multiunit (tandem) embodiment theinvention.

FIG. 6 shows the effects of a poly(methyl methacrylate) coating with andwithout a central, uncoated, fill thickness opening on in vitrohyromorphone release from the device.

FIG. 7 shows the effect of alterations in the height of the cylindricaldevice with constant hole and device diameters on in vitro hydromorphonerelease from the poly(methyl methacrylate)-coated device.

FIG. 8 demonstrates that hydromorphone release from the delivery deviceof the subject invention exhibited near zero-order kinetics in vitro forup to 4 weeks. The initial release "burst" that complicates manycontrolled delivery devices was eliminated.

FIG. 9 shows that flexibility in the amount of hydromorphone releasedper hour and the duration of hydromorphone delivery in vitro was easilyachieved through simple modifications of the delivery devices.

FIG. 10 shows that 2 delivery devices placed subcutaneously in each of 5rabbits produced stable, sustained plasma hydromorphone concentrationsfor up to 4 weeks. These plasma concentrations were within the humantherapeutic range.

FIG. 11 shows the predicted hydromorphone release from multipleimplanted delivery devices and the observed plasma hydromorphoneconcentrations in rabbits over time. Increasing the number ofsubcutaneously implanted delivery devices produced a sustained andpredictable increase in rabbit plasma hydromorphone concentrations.Systemic toxicity with 6 implants (approximately 900 μg/hrhydromorphone) was limited to transiently increased sedation anddecreased oral intake.

FIG. 12 shows that subcutaneously implanted osmotic pumps that deliveredapproximately the same amount of hydromorphone per hour as two deliverydevices of the invention, produced comparable rabbit plasmahydromorphone concentrations.

FIG. 13 shows an intravenous bolus equal to 50% (600 μg) and 100% (1200μg) of the cumulative amount of hydromorphone released by two deliverydevices over 4 hours (a typical human dosing interval) produced peakrabbit plasma concentrations within one minute followed by a rapid fallto baseline over several hours. Peak plasma hydromorphone concentrationswere well tolerated and at least 4 times higher than the steady-stateconcentration obtained with the device of the invention.

DETAILED DESCRPTION OF THE INVENTION

The subject invention relates to a biocompatible, non-inflammatory, andnon-biodegradable implant device 2 which permits controlled release of apotent opioid by subcutaneous implant. A drug such as hydromorphone isimbedded in a controlled release matrix 14 such as polyethylene-vinylacetate, and this polymer is coated with the biocompatible andhydromorphone impermeable polymer 12 such as poly(methyl methacrylate).The implant typically has a cylindrical geometry with a diameter of thetop 4 and bottom 6 of the cylinder, greatly exceeding height of theoutside wall 8 of the cylinder. The implant 2 is perforated creating anopening 10 in the top 4 and bottom 6 of the device 2 and creating anuncoated internal cylindrical wall 16. This structure permits steadyrelease of hydromorphone.

The delivery device of the invention minimizes the opportunity for drugdiversion, improves compliance, and eliminates the need for expensivesupport personnel and equipment, and the need for expensive and oftenunavailable external catheters and pumps in patients with cancer-relatedpain who require continuous opiate administration. The device deliversstable amounts of hydromorphone in vitro and in vivo for prolongedperiods of time. The plasma hydromorphone levels achieved by the subjectinvention produce no significant toxicity. The steady levels achievedreduce toxicity and improve efficacy. The plasma hydromorphone levelsand the variability in those levels achieved with implants is quitesimilar to the values obtained with osmotic pumps.

The coating 12 of the EVA polymer containing drug effectively eliminatesthe initial "burst" of drug release seen with many other deliverydevices. Unlike intravenous bolus administration, the plasmahydromorphone levels obtained after device implantation remain stableand within the therapeutic range for the entire dosing interval.

Variations in the thickness (i.e., height of wall 8) and diameter (i.e.,diameter of top 4 and bottom 6) of these devices as well as in thenumber of devices implanted provides flexibility in the amount ofhydromorphone released per hour, and duration of hydromorphone release,and the magnitude of the plasma hydromorphone levels obtained.

The subject invention solves the problem of the "burst effect" forhydromorphone, eliminates repeated injections of hydromorphone, providesa longer term management for stable and/or chronic cancer pain, providesa means to treat opioid drug addiction, and prevents abuse of thenarcotic, i.e., drug diversion, since the technology makes it extremelydifficult to extract the hydromorphone from the device of the invention.

The Opioid

Hydromorphone (including hydromorphone hydrochloride) is a watersoluble, potent (6-7 times more potent than morphine) opioid approvedfor subcutaneous use and commonly administered to patients withcancer-related pain. Vallner et al, J. Clin. Pharmacol 21:152-6, 1981,Bruera et al, J. Natl. Cancer Inst., 80:11524, 1988, Reidenberg et al,Clin. Pharmacol Ther., 44:376-82, 1988, Moulin et al, Can. Med. Assoc.J., 146:891-7, 1992, Moulin et al, Lancet, 337:465-8, 1991. Constraintson the size of a subcutaneous delivery device favor the use of thisopioid. Hydromorphone has excellent water solubility and gives favorablepattern of release from hydrophobic EVA polymer.

The Matrix

Ethylene vinyl acetate (EVA) copolymer is a biocompatible,noninflammatory, and nonbiodegradable polymer. A non-biodegradablepolymer is used in the subject invention to permit localization.Further, if any untoward circumstance should force a physician to takeout the implant 12 from a patient, it can be taken out intact. Abiodegradable implant will soften and lose its structural integrity overtime, making the task of emergency removal difficult, if not impossible.

Drug-loaded EVA matrices are advantageously fabricated by a solventcasting technique. The polymer is first dissolved in an organic solvent,preferably a low boiling solvent such as methylene chloride orchloroform to facilitate eventual removal of the solvent by evaporation.The concentration of the polymer solution advantageously ranges fromfive to fifteen weight percent. Too dilute a concentration leads tobubble formation during the casting and too concentrated makes itdifficult to disperse the drug particles in the solution.

The drug to be embedded in the EVA matrix is dissolved, or in the case ahigh loading drug level, dispersed in the polymer solution. The drug canbe released by permeation through the polymer phase, or if the drug hasa low solubility in the polymer, released by diffusion through the poresand channels. As the drug particles near the surface of the matrix aredissolved and released, they leave behind pores and channels throughwhich the embedded drug particles are released. Preferably, the drugparticles are sieved, since the size of the drug particles determinesthe size of the pores and channels. This however is not absolutelynecessary unless the drug particles aggregate to form large clumps, forexample, several hundred microns in size. Reasonably reproduciblerelease kinetics (i.e., near constant delivery) are obtained withcommercially available drug particles which have been micronized.

The polymer solution with drug is then cast into a mold of the desiredshape and size. After slow evaporation of the solvent (to prevent bubbleformation), the drug molecules or drug particles are embedded in thepolymer matrix. The casting is normally done at low temperatures toprevent sedimentation of the drug particles during the solventevaporation. Typically the polymer solution with drug is poured into amold that has been cooled to a temperature below the melting point ofthe solvent. The solution is hence rapidly frozen to allow uniformdispersion of the drug particles in the final matrix.

Other materials suitable for uses as the matrix include silicone rubber,hydrogels such as crosslinked poly(vinyl alcohol) and poly(hydroxyethylmethacrylate).

Coating

Coating the EVA polymer matrix eliminates the potentially deadly "bursteffect" normally seen with controlled release devices. An uncoatedpolymer delivers hydromorphone in a burst or spike within the first twodays of drug administration, and then tapers down to a minimum in theensuing days (see FIG. 6). This is a key problem in using subcutaneousimplants for drug delivery, and the subject invention solves the problemfor hydromorphone. To eliminate the burst effect and to obtain moresteady or constant release kinetics without manipulation of non-uniformdrug distribution in the matrix, the EVA polymer contaning the drug 14is coated, except a small opening 10 in the middle, with a coating 12impermeable to the drug, and tissue biocompatible so as to invoke onlyminimal fibrous tissue encapsulation of the implant 2. Advantageously,the bone cement poly(methyl methacrylate) is used with hydromorphone.The coating 12 should be thick enough for the intended life of theimplant, typically about 100 microns.

Coating of the matrix is advantageously achieved by the dip-coatingtechnique. For example, a coating is applied by impaling the disk on asyringe needle of a chosen diameter and dipping into a polymer solution.After application of several coatings by repeated dip-coating anddrying, the needle is removed to expose an uncoated cylindricalaperture. Alternatively, an opening along the axis of the matrix iscreated after coating the matrix. Drug is released only through thisopening. With this configuration, a near constant release of drug isobtained without a drug concentration gradient in EVA polymer.

The coating material is impermeable to hydromorphone. non-biodegradable(negligible cleavage of the polymer backbone or mass loss within atwo-month period), and soluble in a solvent that is not a good solventfor the selected matrix. Otherwise, the matrix might partially dissolveduring the dip-coating and some of the drug molecules or particles mightbe embedded in the coating. The solubility parameter of poly(methylmethacrylate) is 9-9.5 [cal/cm³ ]⁰.5. Other polymers with thissolubility parameter which are impermeable to hydromorphone are suitablecoatings for the EVA-hydromorphone polymer.

Drug Loading

The ratio of hydromorphone to EVA polymer is 10-90% by weighthydromorphone, advantageously 30-70%. The drug/EVA mixture ishomogeneous. The higher levels of hydromorphone concentration aretypically used where the opening 10 is very small (see below).

Implant Geometry

The implant is advantageously cylindrical in shape (see FIGS. 1 and 2).Other geometries where the distance between the uncoated wall and thecoated wall (opposite the uncoated wall) remains constant orsubstantially (± 20%) constant throughout the implant, can be used,e.g., a hemisphere where the uncoated wall is in the shape of ahemisphere (FIG. 3), or a cube having a square opening which extends thefull height (thickness) of the cube (FIG. 4). These geometries provide anear constant release rate over the life of the implant.

The cylindrical implant is 5-100 mm, advantageously 10-25 mm, indiameter and 1-20 mm, advantageously 1-2 mm in height (thickness).

A single 50 micron--3 mm diameter, advantageously 0.5-1.5 mm diameter,circular or substantially circular opening 10 extends along the axis ofthe cylindrical device, creating an internal cylindrical uncoated area16 through which the drug is released. The area of the opening forcylinder, cube, hemisphere or other shape devices, is less than 10%,advantageously less than 1%, of the surface area of the top of thedevice.

Multiple unit devices of the invention are formed by juxtaposingcylindrical implants (or other shapes), i.e., where the axes of theindividual devices are perpendicular to the axis of the multiple unitdevice. (See FIG. 5). In the case of a juxtaposed arrangement, the areaof contact (i.e., where the units are joined) between individualcomponents (e.g., individual cylinders or cubes) may be coated oruncoated.

In another embodiment, multiple unit devices are formed where the axesof the individual devices (e.g., cylindrical or cubic) are the same asthe axis of the multiple unit device. In order to join individualdevices in this way and permit release of drug, the individual devicesare spaced apart and linked by means of spacers. In one embodiment, thespacers are one or more members running parallel to the multiple unitaxis; each of such spacers is attached to the outside wall of eachindividual device. Alternatively, porous members are alternated betweenindividual devices (and join the devices). In a further embodiment,small spacers contacting (and joining) the bottom of one individualdevice and the top of the adjacent device are used to form multiple unitdevices. Spacers advantageously are made using the coating material,e.g., poly(methyl methacrylate). In another embodiment, wire coated withthe coating material is used as the spacer.

Administration of the Implant

The device of the invention 12 is implanted subcutaneously,advantageously in the upper arm or abdominal areas, using proceduresknown to those skilled in the art. The dose rate chosen is that which issafe and efficacious for a particular patient. Too low a dose rateresults in a lack of pain relief, and too great a dose rate results insedation followed by respiratory depression. For example, in cancer paintreatment, using a visual analog scale for measuring the pain, andtitrating hydromorphone to the patient's subjective level of pain, adisk of appropriate dose rate is chosen for a patient.

For treatment of cancer pain, implants are typically designed to producefrom 0.1-25 mg/hr., advantageously, 0.1 to 10 mg/hr (e.g., 0.25 mg/hr, 1mg/hr and 4 mg/hr). One to three implants are typically placed inpatients. Dose (mg/hr) is advantageously regulated by the height of thecylindrical disk or opening diameter, i.e., increased height or openingdiameter means larger release rates (a greater uncoated surface area 16remains exposed to the external milieu). See FIG. 7. Delivery ofmultiple implants, either individually or juxtaposed as described above,increases dose rate. Further, increasing drug load increases dose rate.

For treatment of opioid dependence, implants are typically designed toproduce 0.1-0.5 mg/hr hydromorphone per hour subcutaneously. For adiscussion of methadone maintenance see Strain et al, Ann. Intern. Med.119 23-27 (1993), and Gerstein and Lewin, N. Engl. J. Med., 323, 844-848(1990).

The device can control the release of hydromorphone to desired bloodlevels for periods of two weeks to in excess of six months. The lifetimeof an implant is advantageously regulated by its diameter (increaseddiameter increases lifetime). Drug loading, opening size and height alsohave an effect on the lifetime of the implant. An implant lasting fourweeks is advantageous for cancer pain treatment since an oncologist willusually evaluate his cancer patient with chronic pain at least once amonth. The degree of pain may increase due to a progressive tumornecessitating a higher dose. Moreover, there is tolerance tohydromorphone such that higher doses may be needed to control the samedegree of pain in the succeeding month.

The device of the subject invention provides near constant delivery ofhydromorphone. "Near constant" is defined as ± a 5 fold (500%),advantageously ± a two fold (200%) variation, most advantageously ±single fold (100%) variation in the target delivery rate (in vivo or invitro). A greater than 5 fold variation results in a "burst effect"which could cause damage or even death to the recipient.

In one embodiment of the invention, the drug release from the implant issupplemented with additional delivery (oral, rectal etc.) of an opiatewhen the patient is experiencing heightened pain.

Treatment of Pain

The implant of the invention can be used in any case where oral opiatesare indicated. In about 85% of patients with cancer pain, oral opiatesare indicated. The invention is particularly advantageous where oraladministration is not appropriate or available or where there istoxicity from intermittent administration. The implant of the inventionhas application in the treatment of cancer pain in humans or in otheranimals. The implant has utility in the treatment of other types ofchronic pain such as chronic severe pain resulting from degenerativemusculoskeletal or nervous system diseases.

Treatment of Opioid Dependence

The implant of the invention is useful in the treatment of opioid drug(e.g., heroin) addiction. Hydromorphone given in low dosages overextended periods of time is effective in the treatment of drugaddiction. The implant of the invention can be used in any situationwhere a methadone maintenance program could be used. The implant insuresthat low dose rates of the drug can be sustained for extended periodswithout dependence on patient compliance with oral dose schedules.Further use of the implant provides drug in a form which virtuallyeliminates the possibility of illicit use.

The following Examples are illustrative, but not limiting of thecompositions and methods, of the present invention. Other suitablemodifications and adaptations of a variety of conditions and parametersnormally encountered in clinical therapy which are obvious to thoseskilled in the art are within the spirit and scope of this invention.

EXAMPLES Example 1

Polymer Formulation

A low temperature solvent casting technique was used to formulate thehydromorphone implants used in these experiments. EVA (MW about 250,000)(Elvax-40W. Dupont) with 40% by weight of vinyl acetate, was cleaned inwater and dissolved in methylene chloride (CH₂ Cl₂) to produce a 10%solution. The polymer can be purified by extraction with distilled waterin a Soxhlet extractor for three days, followed by extraction withacetone for another four days to remove impurities and anti-oxidants.The hydromorphone-incorporated matrices were prepared by solventcasting. A 10% (w/v) solution of EVA was made by dissolving 2 gm of pureEVA in 20 ml of methylene chloride.

Non-sieved hydromorphone hydrochloride powder (Knoll Pharmaceuticals)was added at room temperature to the 10% EVA to produce a 50weight-percent solution which was then magnetically stirred forapproximately 10 minutes. Hydromorphone powder can be mechanicallysieved to a predetermined range of particle size and suspended in theEVA solution. Any visible macroscopic clumps remaining in this solutionwere broken apart with a glass stirring rod.

The homogeneous suspension was quickly poured into a recrystallizationdish 14 cm in diameter prechilled to -78° C. on dry ice. The dish wascovered to minimize condensation. After solidification, which occurredwithin 15 minutes, the sample was dried in two 48-hour stages: first at-20° C., and then under vacuum at room temperature.

Hydromorphone polymer disks were cut from the dried circular slab with anumber 7 cork borer to yield approximately 15 polymers of about 0.27 cmthickness and 1.05 cm diameter. For those experiments designed todemonstrate flexibility in the amount of hydromorphone released perhour, double and triple thickness polymers were prepared (0.55-0.65 cmand 0.83 cm thick, respectively) by doubling or tripling the amount ofEVA-hydromorphone mixture placed in the mold. Polymers of 2.13 cmdiameter were also cut from the dried EVA-hydromorphone slab using anumber 15 cork borer to demonstrate flexibility in duration of drugrelease.

Example 2

Polymer Coating

Prior to coating, an 18 gauge hollow steel needle was passed through thefull thickness of each EVA-hydromorphone polymer at approximately thecenter of the circular face of the polymer. Each polymer was then"dipcoated" in a 10% poly(methyl methacrylate) (MW about 996,000)(Aldrich) solution in acetone for 10 seconds. The poly(methylmethacrylate) coating was allowed to air dry at room temperature for 24hours at which time the needle was removed, the polymer was turned over,and the needle was passed back through the central hole in the polymerin the opposite direction. This procedure was then repeated twoadditional times to produce a triple thickness impermeable coating ofpoly(methyl methacrylate) that fully encased each polymer with theexception of an 18 gauge cylinder (about 1.25 mm diameter) passingthrough the center of each polymer, much like a button hole in a button.The coating thickness was about 100-200 μm. The solubility parameter ofthe coating material is 9-9.5 [cal/cm³ ]⁰.5.

Example 3

In Vitro Release Assay

Hydromorphone release from the coated EVA-hydromorphone polymers wasassessed in vitro by placing each polymer in a glass scintillation vialcontaining 10 ml of pH 7.4 0.1M sodium phosphate buffer warmed to 37° C.All vials were placed in a water bath at 37° C. At appropriateintervals, the buffer in each vial was collected and stored incentrifuge tubes at about 4° C. and 10 ml of fresh phosphate buffer at37° C. was added back to each vial. Samples were periodically assayed inbulk on a UV spectrophotometer at 254 nm in matched cuvettes zeroedagainst blank 0.1M pH 7.4 phosphate buffer. Hydromorphone standards wereincluded in each assay and, when necessary, samples were diluted inbuffer such that their absorbance could be measured on the linear partof the standard curve.

The coated EVA-hydromorphone polymers released hydromorphone at aconstant mean rate of 164 μg/hr beginning 4 days after in vitro releaseand continuing for over 4 weeks. Coating these polymers with animpermeable layer of poly(methyl methacrylate) except for the centralfull thickness hole eliminated the initial "burst" that complicates manyother controlled delivery devices. Flexibility in the amount ofhydromorphone delivered per hour and the duration of drug delivery waseasily achieved by varying the thickness and diameter of the coatedEVA-hydromorphone polymers. See FIG. 9.

In Vivo Experiments

Example 4A

Polymer Release

Under general anesthesia, two coated EVA-hydromorphone polymers wereplaced in a subcutaneous pocket in each of five adult rabbits. Rabbitswere housed one to a cage and fed rabbit chow and water ad libitum.Blood samples were drawn from each animal prior to implantation and atappropriate intervals thereafter for up to 6 weeks after placement.Blood samples were centrifuged and plasma was removed and stored in afreezer at -20° C. Plasma samples were assayed in bulk using acommercially available radioimmunoassay opiate screen and hydromorphonestandards. In an attempt to demonstrate a relationship between theamount of hydromorphone implanted and the resultant plasma drug levels,two additional rabbits each had 3 sets of 2 polymers sequentiallyimplanted at approximately one week intervals. The previously implantedcoated polymers were left in place so that the rabbits had 2 then 4 then6 polymers delivering hydromorphone at the same time. Blood was removedand plasma was assayed as described above.

Two devices placed subcutaneously in rabbits produced stable andsustained plasma hydromorphone levels of 23-37 ng/ml for up to 4 weeks(see FIG. 10). Increasing the number of subcutaneous implants in anindividual rabbit produced a sustained and predictable increase in thatrabbit's plasma hydromorphone concentration (see FIG. 11). Nosignificant toxicity was observed in these animal experiments with theexception of mild transient sedation after the implantation of 2 devicesand increased sedation with decreased oral intake after the implantationof larger numbers of devices that also appeared to be transient.

Example 4B

Osmotic Pump Release

In order to validate the rabbit plasma hydromorphone levels measuredafter device implantation, Alzet osmotic pumps were prepared thatdelivered approximately the same amount of hydromorphone per hour as twodevices of the invention. Under general anesthesia, an Alzet osmoticpump (mean pumping rate=2.08 μl/hr, mean fill volume=2073 μl) was placedsubcutaneously in each of 4 rabbits and blood samples were collected asdescribed above. Plasma was also prepared and analyzed as describedabove.

Alzet osmotic pumps that are designed to deliver 297 μg/hr ofhydromorphone produced mean rabbit plasma hydromorphone levels 28 to 51ng/ml over a 2 week period (see FIG. 12).

Example 4C Hydromorphone Intravenous Boluses

Single 600 μg and 1200 μg boluses (equal to 1/2 to 1 times thecumulative amount delivered subcutaneously by polymers or pumps over 4hours, a typical dosing interval in humans) were administeredintravenously to two additional rabbits and samples were collected at 0,1, 2, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210 and 240 minutes.

Six hundred and 1200 μg hydromorphone boluses produced peak rabbitplasma hydromorphone levels of almost 200 and over 250 ng/ml at oneminute with a rapid fall back to baseline by 4 hours (see FIG. 13).

It will be readily apparent to those skilled in the art that numerousmodifications and additions may be made to both the present invention,the disclosed device, and the related system without departing from theinvention disclosed.

What is claimed is:
 1. A subcutaneous delivery system comprising:i) abicompatible polymeric matrix material, ii) a therapeutic agenthomogeneously embedded in said matrix, and iii) A polymeric coatingsurrounding said matrix impermeable to the therapeutic agent whereinsaid delivery system is cylindrical, cubical or a hemisphere in shapeand has an uncoated internal wall opposite a coated external wall,wherein the distance between said internal uncoated wall and said coatedexternal wall remains substantially constant throughout the deliverysystem, and wherein said delivery system is adapted to deliver saidtherapeutic agent through an opening formed by said internal uncoatedwall at a near constant rate.
 2. A delivery system as in claim 1 whereinsaid delivery system is cylindrical in shape and has a cylindricalshaped opening along the axis of said delivery system forming aninternal wall in said delivery system.
 3. A delivery system as in claim1 wherein said cylindrical shaped opening has a diameter of 0.05-3 mm.4. A method of providing a delivery system comprisingi) implanting atherapeutic agent in a polyethylene vinyl acetate matrix, ii) formingsaid matrix into a cylinder, iii) coating said matrix with poly(methylmethacrylate) forming an external coated wall, and iv) creating acylindrical opening along the axis of the cylindrical matrix creating aninternal uncoated wall in said matrix, wherein the distance between saidinternal uncoated wall and said external uncoated wall opposite saidinternal uncoated wall remains substantially constant throughout thedelivery system, and wherein said delivery system is adapted to deliversaid therapeutic agent at a near constant rate.
 5. A delivery system asin claim 1 wherein said polymeric matrix material is polyethylene-vinylacetate.
 6. A delivery system as in claim 1 wherein said therapeuticagent is hydromorphone.
 7. A delivery system as in claim 1 wherein saidcoating is hydromorphone impermeable.
 8. A delivery system as in claim 1wherein the thickness of said coating is 0.1-1 mm.
 9. A delivery systemas in claim 1 wherein said matrix contains 50% by weight hydromorphoneand 50% by weight poly(ethylene-vinyl acetate).
 10. A delivery system asin claim 9 wherein said hydromorphone is homogeneously distributed insaid matrix.
 11. A delivery system as in claim 1 wherein the height is1-20 mm and the diameter is 5-100 mm.
 12. A multiple unit deliverysystem comprising at least two delivery devices as in claim 1, whereinsaid devices are juxtaposed.
 13. A method of providing prolonged reliefof pain in a mammal suffering from pain comprising subcutaneouslyadministering the device of claim 1 to said mammal.
 14. A method as inclaim 13 wherein said pain is cancer pain.
 15. A method of treatingopioid drug addiction in a mammal having such an addiction comprisingsubcutaneously administering the device of claim 10 to said mammal. 16.A delivery system according to claim 1 wherein said therapeutic agent isan opioid.
 17. A delivery system according to claim 1 wherein saidcoating is poly(methylmethacrylate).